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The role of aldehyde dehydrogenase 2 in cardiovascular disease

Nature Reviews Cardiology volume 20, pages 495–509 (2023)Cite this article

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Abstract

Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme involved in the detoxification of alcohol-derived acetaldehyde and endogenous aldehydes. The inactivating ALDH2 rs671 polymorphism, present in up to 8% of the global population and in up to 50% of the East Asian population, is associated with increased risk of cardiovascular conditions such as coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary arterial hypertension, heart failure and drug-induced cardiotoxicity. Although numerous studies have attributed an accumulation of aldehydes (secondary to alcohol consumption, ischaemia or elevated oxidative stress) to an increased risk of cardiovascular disease (CVD), this accumulation alone does not explain the emerging protective role of ALDH2 rs671 against ageing-related cardiac dysfunction and the development of aortic aneurysm or dissection. ALDH2 can also modulate risk factors associated with atherosclerosis, such as cholesterol biosynthesis and HDL biogenesis in hepatocytes and foam cell formation and efferocytosis in macrophages, via non-enzymatic pathways. In this Review, we summarize the basic biology and the clinical relevance of the enzymatic and non-enzymatic, tissue-specific roles of ALDH2 in CVD, and discuss the future directions in the research and development of therapeutic strategies targeting ALDH2. A thorough understanding of the complex roles of ALDH2 in CVD will improve the diagnosis, management and prognosis of patients with CVD who harbour the ALDH2 rs671 polymorphism.

Key points

  • Aldehyde dehydrogenase 2 (ALDH2) detoxifies alcohol-derived acetaldehyde and lipid peroxidation-generated aldehydes, and its inactivating rs671 polymorphism is present in up to 50% of the East Asian population.

  • The ALDH2 rs671 polymorphism has been clinically and experimentally associated with an increased risk of cardiovascular disorders, including coronary artery disease, alcohol-induced cardiac dysfunction, pulmonary artery hypertension, heart failure and drug-induced cardiotoxicity.

  • Carriers of the ALDH2 rs671 polymorphism are at lower risk of ageing-related cardiac dysfunction and aortic aneurysm or dissection compared with those without it, illustrating opposing roles of different ALDH2 genotypes in the pathogenesis and progression of cardiovascular disease.

  • ALDH2 can also modulate risk factors associated with atherosclerosis, such as cholesterol biosynthesis and HDL biogenesis in hepatocytes and foam cell formation and efferocytosis in macrophages, via non-enzymatic pathways.

  • Given the ubiquitous nature of ALDH2, further mechanistic insight into cellular and organ-level functions is needed to design safe and effective interventions to activate or inhibit ALDH2 to prevent or treat cardiovascular disease.

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Fig. 1: Timeline of research on ALDH2 in cardiovascular disease.
Fig. 2: Overview of the cardiovascular effects associated with the ALDH2*2 allele.
Fig. 3: Overview of the non-enzymatic and enzymatic roles of ALDH2 in coronary artery disease.
Fig. 4: Role of ALDH2 in myocardial ischaemia and related heart failure.
Fig. 5: Role of ALDH2 in pulmonary arterial hypertension and aortic aneurysm or dissection.

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Acknowledgements

The authors were supported by the National Natural Science Foundation of China (81873950, 82072144, 81772036, 81873953, 82002017, 82102290, 32030053 and 32150710522), the State Key Program of the National Natural Science Foundation of China (82030059), the National Key R&D Program of China (2020YFC1512700, 2020YFC1512705 and 2020YFC1512703), the Taishan Young Scholar Program of Shandong Province (tsqn20161065 and tsqn201812129), the Taishan Pandeng Scholar Program of Shandong Province (tspd20181220), the Clinical Research Center of Shandong University (2020SDUCRCB003), the National S&T Fundamental Resources Investigation Project (2018FY100600 and 2018FY100602) and the Interdisciplinary Young Researcher Groups Program of Shandong University (2020QNQT004).

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Author notes

  1. These authors contributed equally: Jian Zhang, Yunyun Guo, Xiangkai Zhao.

Authors and Affiliations

  1. Department of Emergency Medicine, Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Shandong, China

    Jian Zhang, Yunyun Guo, Xiangkai Zhao, Jiaojiao Pang, Chang Pan, Jiali Wang, Shujian Wei, Yuguo Chen & Feng Xu

  2. Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary–Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Shandong, China

    Jian Zhang, Yunyun Guo, Xiangkai Zhao, Jiaojiao Pang, Chang Pan, Jiali Wang, Shujian Wei, Yuguo Chen & Feng Xu

  3. Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Shandong, China

    Jian Zhang, Yunyun Guo, Xiangkai Zhao, Jiaojiao Pang, Chang Pan, Jiali Wang, Shujian Wei, Cheng Zhang, Yuguo Chen & Feng Xu

  4. Key Laboratory Experimental Teratology of the Ministry of Education, Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Shandong, China

    Xiao Yu

  5. Department of Cardiology, Qilu Hospital of Shandong University, Shandong, China

    Cheng Zhang

  6. Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Innovation Center for Intervention of Chronic Disease and Promotion of Health, Chinese Academy of Sciences, Shanghai, China

    Huiyong Yin

  7. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Huiyong Yin

  8. Department of Biomedical Sciences, City University of Hong Kong, Hong Kong SAR, China

    Huiyong Yin

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Contributions

J.Z., Y.G., X.Z., Y.C., H.Y. and F.X. wrote the manuscript; J.Z., Y.G., X.Z., J.P., Y.C., H.Y. and F.X contributed substantially to the discussion of its content; and J.Z., Y.G., X.Z., C.P., J.W., S.W., X.Y., C.Z., Y.C., H.Y. and F.X. reviewed and edited the manuscript before submission.

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Correspondence to Yuguo Chen, Huiyong Yin or Feng Xu.

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Zhang, J., Guo, Y., Zhao, X. et al. The role of aldehyde dehydrogenase 2 in cardiovascular disease. Nat Rev Cardiol 20, 495–509 (2023). https://doi.org/10.1038/s41569-023-00839-5

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